Human Osteoclast-Poor Osteopetrosis with Hypogammaglobulinemia due to TNFRSF11A (RANK) Mutations

Abstract

Autosomal-Recessive Osteopetrosis (ARO) comprises a heterogeneous group of bone diseases for which mutations in five genes are known as causative. Most ARO are classified as osteoclast-rich, but recently a subset of osteoclast-poor ARO has been recognized as due to a defect in TNFSF11 (also called RANKL or TRANCE, coding for the RANKL protein), a master gene driving osteoclast differentiation along the RANKL-RANK axis. RANKL and RANK (coded for by the TNFRSF11A gene) also play a role in the immune system, which raises the possibility that defects in this pathway might cause osteopetrosis with immunodeficiency. From a large series of ARO patients we selected a Turkish consanguineous family with two siblings affected by ARO and hypogammaglobulinemia with no defects in known osteopetrosis genes. Sequencing of genes involved in the RANKL downstream pathway identified a homozygous mutation in the TNFRSF11A gene in both siblings. Their monocytes failed to differentiate in vitro into osteoclasts upon exposure to M-CSF and RANKL, in keeping with an osteoclast-intrinsic defect. Immunological analysis showed that their hypogammaglobulinemia was associated with impairment in immunoglobulin-secreting B cells. Investigation of other patients revealed a defect in both TNFRSF11A alleles in six additional, unrelated families. Our results indicate that TNFRSF11A mutations can cause a clinical condition in which severe ARO is associated with an immunoglobulin-production defect.

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

“…3. Furthermore, these studies showed that only mature osteoclasts produce the anabolic signal (76) and hence illustrated the specificity of this phenomenon, while also providing some evidence as to why bone formation appears very low or even missing in the absence of osteoclasts, as seen in the RANK-deficient patients (78). However, controversies still exist, as demonstrated recently where inhibition of bone resorption in vitro with the V-ATPase inhibitor bafilomycin blunted release of anabolic factors from the bone matrix (79).…”

“…This definition focuses on the resorptive side of bone remodeling, however, and recognizes direct (for example, ADO due to ClC-7 defects within the osteoclast) and indirect regulatory defects. Examples of the latter are defects in the receptor for RANKL at the resorptive, osteoclastic site (RANK) (78), and mutations in RANKL by itself on the osteoblastic site (210). This definition acknowledges regulatory (autocrine/ paracrine/endocrine) pathways within bone remodeling and also points to the fact that bone formation is ongoing in osteopetrosis.…”

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

“…This result might reflect the potential regulatory function of rs8086340 SNP, which is in such strong LD with the rs4574025 that conditioning on either SNP gave almost identical residual P values (<0.004). Variants of TNFRSF11A (RANK) underlie a familial form of Paget disease of the bone (46) and a recessive form of osteopetrosis with hypogammaglobulinemia (47). TNFRSF11A variants are also im- Table 4.…”

SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity

“…(1,(5)(6)(7)(8)(9)(10) The SNX10 gene was amplified using primers and conditions kindly provided by Aker and colleagues (Hebrew University Medical Center, Jerusalem). The mutation nomenclature conforms to www.hgvs.org/mutnomen.…”